4 research outputs found
Integrative Toxicoproteomics Implicates Impaired Mitochondrial Glutathione Import as an Off-Target Effect of Troglitazone
Troglitazone,
a first-generation thiazolidinedione of antihyperglycaemic
properties, was withdrawn from the market due to unacceptable idiosyncratic
hepatotoxicity. Despite intensive research, the underlying mechanism
of troglitazone-induced liver toxicity remains unknown. Here we report
the use of the <i>Sod2</i><sup><i>+/–</i></sup> mouse model of silent mitochondrial oxidative-stress-based
and quantitative mass spectrometry-based proteomics to track the mitochondrial
proteome changes induced by physiologically relevant troglitazone
doses. By quantitative untargeted proteomics, we first globally profiled
the <i>Sod2</i><sup><i>+/–</i></sup> hepatic
mitochondria proteome and found perturbations including GSH metabolism
that enhanced the toxicity of the normally nontoxic troglitazone.
Short- and long-term troglitazone administration in <i>Sod2</i><sup><i>+/–</i></sup> mouse led to a mitochondrial
proteome shift from an early compensatory response to an eventual
phase of intolerable oxidative stress, due to decreased mitochondrial
glutathione (mGSH) import protein, decreased dicarboxylate ion carrier
(DIC), and the specific activation of ASK1-JNK and FOXO3a with prolonged
troglitazone exposure. Furthermore, mapping of the detected proteins
onto mouse specific protein-centered networks revealed lipid-associated
proteins as contributors to overt mitochondrial and liver injury when
under prolonged exposure to the lipid-normalizing troglitazone. By
integrative toxicoproteomics, we demonstrated a powerful systems approach
in identifying the collapse of specific fragile nodes and activation
of crucial proteome reconfiguration regulators when targeted by an
exogenous toxicant
Integrative Toxicoproteomics Implicates Impaired Mitochondrial Glutathione Import as an Off-Target Effect of Troglitazone
Troglitazone,
a first-generation thiazolidinedione of antihyperglycaemic
properties, was withdrawn from the market due to unacceptable idiosyncratic
hepatotoxicity. Despite intensive research, the underlying mechanism
of troglitazone-induced liver toxicity remains unknown. Here we report
the use of the <i>Sod2</i><sup><i>+/–</i></sup> mouse model of silent mitochondrial oxidative-stress-based
and quantitative mass spectrometry-based proteomics to track the mitochondrial
proteome changes induced by physiologically relevant troglitazone
doses. By quantitative untargeted proteomics, we first globally profiled
the <i>Sod2</i><sup><i>+/–</i></sup> hepatic
mitochondria proteome and found perturbations including GSH metabolism
that enhanced the toxicity of the normally nontoxic troglitazone.
Short- and long-term troglitazone administration in <i>Sod2</i><sup><i>+/–</i></sup> mouse led to a mitochondrial
proteome shift from an early compensatory response to an eventual
phase of intolerable oxidative stress, due to decreased mitochondrial
glutathione (mGSH) import protein, decreased dicarboxylate ion carrier
(DIC), and the specific activation of ASK1-JNK and FOXO3a with prolonged
troglitazone exposure. Furthermore, mapping of the detected proteins
onto mouse specific protein-centered networks revealed lipid-associated
proteins as contributors to overt mitochondrial and liver injury when
under prolonged exposure to the lipid-normalizing troglitazone. By
integrative toxicoproteomics, we demonstrated a powerful systems approach
in identifying the collapse of specific fragile nodes and activation
of crucial proteome reconfiguration regulators when targeted by an
exogenous toxicant
Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans
RNA Editing of the IQ Domain in Ca v1.3 Channels Modulates Their Ca 2+-Dependent Inactivation
10.1016/j.neuron.2011.11.022Neuron732304-316NERN